Challenges in assigning endocrine-specific modes of action: Recommendations for researchers and regulators

As regulatory programs evaluate substances for their endocrine disrupting properties, careful study design and data interpretation is needed to distinguish between responses that are truly endocrine-specific and those that are not. This is particularly important in regulatory environments where criteria are under development to identify endocrine disrupting properties to enable hazard-based regulation. Irrespective of these processes, most jurisdictions use the WHO/IPCS definition of an endocrine disruptor (ED), requiring that a substance is demonstrated to cause a change in endocrine function that consequently leads to an adverse effect in an intact organism. Such a definition is broad, and at its most cautious, might capture many general mechanisms that would not specifically denote an ED. In addition, endocrine responses may be adaptive in nature, designed to maintain homeostasis rather than induce an irreversible adverse effect. The likelihood of indirect effects is increased in (eco)toxicological studies requiring the use of maximum tolerated concentrations or doses, which must produce some adverse effect. The misidentification of indirect effects as truly endocrine mediated has serious consequences for prompting animal- and resource-intensive testing and regulatory consequences. To minimize the risk of misidentification, an objective and transparent weight of evidence (WoE) procedure based on biological plausibility, essentiality, and empirical evidence of key events in an adverse outcome pathway is recommended to describe the modes of action that may be involved in toxic responses in non-target organisms. Confounding factors such as systemic toxicity, general stress, and infection can add complexity to such an evaluation and should be considered in the WoE. A recommended set of questions are proffered to help guide researchers and regulators in discerning endocrine and non-endocrine responses. While many examples provided in this paper are based on ecotoxicology, the majority of the concepts and processes are applicable to both environmental and human health assessments.